Damien Bonnet

Unité médico-chirurgicale de Cardiologie Congénitale et Pédiatrique Hôpital Universitaire Necker Enfants malades – APHP, Université Paris Descartes, Sorbonne Paris Cité

IcarP Cardiology, Institut Hospitalo-Universitaire IMAGINE

Centre de Référence Maladies RaresMalformations Cardiaques Congénitales Complexes-M3C

Centre de Référence Maladies RaresMaladies Cardiaques Héréditaires- CARDIOGEN

Hypertensions pulmonaires de l’enfant

TASK FORCE 12Pediatrics

ERIKA ROSENZWEIG MD, Chair New York, NY USAROLF M. F. BERGER MD, Chair Groningen, THE NETHERLANDS

STEVEN ABMAN, MD Aurora, CO USAIAN ADATIA, MD Edmonton, CANADA

NewguidelinessinceNice2013

Circulation. 2015;132:2037-2099 Heart 2016;102:ii86-ii100.

Specificguidelinesforneonatalpulmonaryhypertension

Time (months)

Sur

viva

l (%

)

00 12 24 36 72 84

20

40

60

80

100

48 60

Children<1 year1,2

Adults2.8 years

1. Houde C, et al. Br Heart J 1993;70:461-8. 2. Barst, RJ, et al. Circulation 1999; 99:1197-208.

Median survival: 2.8 years (n=194)Pediatric median survival: 0.8 years (n=16)

Natural History of IPAH: NIH Registry

RecentlandmarksinpediatricPH

• Extensionofdrugapprovalinchildren(n=1)!

• Expansionofuseofinterventional-surgicalapproachesforend-stagePAHinchildren

• Geneticdiscoveriesrelevanttopediatricpractice

• Newinsightsfrompediatricspecificregistrydata

Definition of pediatric PH/PAH• A mean pulmonary arterial pressure of >25 mmHg with a capillary

wedge pressure of <15mmHg and a PVRi >3WU*m2 in children > 3 months of age with two ventricle anatomy.

• Limited data to extend the definition to children with mean PAP 21-24 mmHg.

• Age is a pending problem:– Definition of PH in children less than 3 months of age– No RHC measure of pulmonary pressure in neonates with PPHN or PH associated with developmental

lung disease

Definition of vasoreactivity in children

Douwes M et al. JACC 2016

Definition of vasoreactivity in children

Douwes M et al. JACC 2016

Heritable PAH in pediatrics

• Known mutations: BMPR2, ALK1, ENG, CAV1, KCNK3, EIF2AK4, TBX4, SOX17

• TBX4 – described potential role in pediatric PAH and small patella syndrome and lung development 1

• SOX17 - role in PAH and cardiac development

1-Kerstjens-Frederikse WS, J Clin Genet 2013 2-Levy M, ERJ, 2016

HeritablePAHinpediatrics• Genetic screening for PAH genes mutations should be performed in children

– in expert centers with a genetic counseling group in all children diagnosed with IPAH and HPAH

• Genetic screening for PAH/lung-cardiac development should be done in APAH-CHD ?– TBX4 and SOX17 genes mutations

• Genetic screening for neonatal pulmonary hypertension is potentially recommended– FOXF1 in alveolo-capillary dysplasia– TBX4 in neonatal respiratory distress and PPHN

• Sharing exception may hold key to future understanding of PH in children

Gräf S et al. Nature Communication 2017

Identification of PAH genes mutations in a pediatric population Results

• No mutations in children with group 3 and type 4 APAH-CHD. • 8 mutations were found in 36 children with iPAH (22%)

– 3 in BMPR2, – 3 in ALK1, – 2 in TBX4. – No mutations were identified in ENG, SMAD9 or KCNK3.

• 4 mutations were found in the 8 fPAH families (50%) – 2 in BMPR2, 1 in ALK1, 1 in TBX4. – only one sibling of an index case with a TBX4 mutation was alive with PAH, and had the same

mutation. In the three remaining families, the first-degree relatives who had PAH were all dead at inclusion of the index case into our study with no material available for genetic testing.

• 2 mutation in EIF2AK4 in the two patients with clinical, hemodynamic and CT features of PVOD.

Lévy M et al. ERJ 2016

Low prevalence of known genes for PAH PAH genes variants and risk of PVD

Gender and PAH Ethnicity Genetic predisposition in CHD • Down syndrome: -comorbid condition in pediatric PAH 13%1

•Noonan syndrome

•BMPR2 mutations in CHD224 mutations were identified, accounting for 22 of the 294 patients with CHD-PVD (7.5%) and 2 of the 161 CHD patients without PVD (1.2%, P=0.004)

Liu et al. Pulm Circ 2017Liu D et al. Int J Cardio 2016

+/- +/- +/-

-/- +/- +/- -/-

-/- -/- +/-

TBX4 c.1119C>G, p.Tyr373*

TBX4 c.781C>T, p.Arg261*

+/-

+/-

+/- -/-

-/-

TBX4 c.231G>A, p.Trp77*

+/--/-

-/- +/- -/- +/- +/-

Genetic counseling : the penetrance problem

PAH+mutation No PAH + mutation

Classification of pediatric PH

3 Main topics

1-Neonatal pulmonary hypertension

2-Developmental lung disorders and PH

3-Congenital heart diseases and PH/PAH

Pathogenesis of PPHN• Maternal NSAID, SSRI use; • Premature closure of the DA• C-section delivery• Post-term (> 41 weeks)• Large for gestational age• Abnormal placenta• Altered lung development • Cardiovascular abnormaliities

• Hyperoxia/oxidative stress• Ventilator Induced Injury• Asphyxia• Inflammation/Infection

PRENATAL FACTORSPOSTNATAL FACTORS

Injury to the Developing Lung Circulation

ImpairedVasoreactivity

DecreasedAngiogenesis

Altered Vascular Structure

Persistent Pulmonary Hypertension of the Newborn - Failure to decrease PVR at birth - Extra-pulmonary shunting across DA, PFO - Severe hypoxemia, Respiratory Failure

Pulmonary Vascular Disease in Developmental Lung DisordersCongenitalDiaphragma0cHernia

PulmonaryInters00alGlycogenosis SurfactantProteinBDeficiency

AlveolarCapillaryDysplasia

(CourtesyCsabaGalambos)

PH in Down syndrome/trisomy 21 is a developmental lung disorder

• PPHN more frequent in Down syndrome• APAH-CHD has an earlier onset in DS

Bush D et al. J Pediatr 2017

Multifactorial pulmonary hypertension in children

Scimitar syndrome

Post-capillary PH

Lung disease

Left-to right shunt/CHD

Systemic supply to the lung

Pulmonary vascular disease

/maladaptation

Multifactorial pulmonary hypertension in scimitar syndrome

Bonnet D et al. 2019

Treatment of pediatric PAH/PH and current challenges

1. AVT responders should receive Calcium channel blockers

Douwes M et al. JACC 2016

Low and high risk pediatric patients with PAHLOWER RISK DETERMINANTS OF RISK HIGHER RISK

No Clinical evidence of RV failure YesNo Progression of Symptoms Yes

> 350 meters 6MWT (>7 yrs old) < 350 metersGrowth Failure to thrive

I,II WHO Functional Class III,IV

Minimally elevated SBNP / NTproBNP Significantly elevated Rising level

Echocardiography

RA / RV Enlargement Reduced LV size

Increased RV/LV Ratio Reduced TAPSE

Low RV FAC Pericardial Effusion

Systemic CI > 3.0 L/min/m2 Systemic venous saturation >65%

+ Acute VasoreactivityHemodynamics

Systemic CI < 2.5 L/min/m2 RAP > 10mmHg

PVRI > 20 WU*m2 Systemic venous saturation < 60%

PACi <0.85

No

General: Consider Diuretics, Oxygen, Anticoagulation

Improved + Sustained reactivity

Oral CCB

Continue CCB

Yes

Negative

Lower Risk Higher Risk

Acute Vasoreactivity Testing

Serial Reassessment***

Positive

ExpertReferral

*Regulatory approval for use in children varies among countries** Expert opinion only

*** Deterioration or not meeting treatment goals

Lung Transplant

Epoprostenol or Treprostinil (IV/SQ)

Consider Early Combination

Potts Shunt Atrial septostomy

ERA or PDE-5i (oral) Oral / inhaled prostacyclin / prostacyclin

agonists Consider combination therapy

(sequential or upfront)

Pediatric IPAH/HPAH Treatment algorithm WSPH 2018

Limited evidence in RCT for this algorithm but convincing registries data

Zijlstra WMH, et al. JACC 2014

Lung transplantation in children(Lung Transplantations: january 1990 – june 2012)

0

25

50

75

100

Years0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Adult (N=43,501) Adult (N=43,501)

Median survival (years): Adult = 5.6; Pediatric = 5.1

p = 0.4400

2014JHLT. 2014 Oct; 33(10): 1025-1033

Pediatric PAHMedian survival 5.8 years

Death on list 7/26: 27%

Goldstein BS et al. J Heart Lung Transplant 2011

Operative death/acute graft failure 22%

Potts shunt in pediatric PAH

• Good long term responders• Still high risk procedure• Need to further define indications/

contraindications• Registry data from PePH association

Blanc J, Vouhe P, Bonnet D. N Engl J Med. 2004 Feb 5;350(6):623

What is the path to demonstrate efficacy of a new compound in pediatric PAH ?

Predictor of outcome 1-is measured at baseline2-its initial value predicts « hard » outcomes (death, transplantation)

Therapeutic target 1-baseline values correlate with outcome2-is in the pathway of the disease3-treatment induces changes in the surrogate value4-changes in the surrogate value modifies outcome

Therapeutic trial endpoint 1-Measure of how the patient behaves, feels, survives2-Measuring the endpoint should do no/limited harm

Treatment Goals in Pediatric PAHWHO-FC NT-pro-BNP TAPSE

Ploegstra MJ et al. Eur Resp J 2015

WHO-FC NT-pro-BNP TAPSE

Component 1 = death Component 2 = lung-transplantation Component 3 = non-elective PAH-related hospitalization Component 4 = initiation of intravenous prostanoid Component 5A = functional deterioration (defined as worsening of WHO-FC only) Component 5AB = functional deterioration (defined as worsening of WHO FCand/or ≥ 15 % decrease in 6-MWD) CW-endpoint = Full composite clinical worsening endpoint consisting of death, lung-transplantation, non-elective PAH related hospitalization, initiation of intravenous prostanoids and functional deterioration.

6 months

Event-free survival of 6 endpoint combinationsOnly the first occurrence of endpoint components

are incorporated as events

Ploegstra MJ et al. Eur Respir J 2015.

Clinical worsening as composite study endpointin pediatric PAH

Disease progression 1 (n = 255)

Disease progression 2 (n = 255)

Disease progression 3 (n = 255)Number of

events121 173 175

Person–years 524.7 396.5 377.6Rate (95% CI) 23.1 (19.3, 27.6) 43.6 (37.6, 50.6) 46.3 (40.0, 53.7)

Death (all-cause) Death (all-cause) Death (all-cause)PAH related

hospitalisation*PAH related

hospitalisation* PAH related

hospitalisation*Lung transplantation Lung transplantation Lung transplantationAtrial septostomy Atrial septostomy Atrial septostomy

WHO FC deterioration† WHO FC deterioration†

Initiation of i.v. / s.c. prostanoids

Initiation of i.v. / s.c. prostanoids

Syncope SyncopePAH worsening

(symptoms)

Association for Paediatric pulmonary hypertension *Increased right heart failure, haemoptysis; †Increase ≥1 WHO FC

Beghetti M, et al. AEPC 2016

0

20

40

60

80

All-cause death Transplantation Initiation of i.v./s.c. prostanoid

1242

33

11

35

58 052

38

11

41

58 000011

78

713

Disease progression 1 (n = 121)Disease progression 2 (n = 173)Disease progression 3 (n = 175)

Disease progression composite outcomes and the first occurring events within these outcomes

Beghetti M, et al. Int J Cardiol 2019

Association for Paediatric pulmonary hypertension *Increased right heart failure, haemoptysis; †Increase ≥1 WHO FC

Designing RCT in pediatrics

• Common approach among regulators (requirements for approval)• Consensus on acceptable clinical endpoints (physicians/regulators)• Use of targeted PAH therapy that does not have established

benefit should not cause lack of equipose• Extrapolation opportunities: adult PAH -> pediatric PAH• Novel trial design / analysis: composite with ranked analysis• Potential clinically meaningful endpoints: TTCW, PROs, Functional

Activity measurements (WHO-FC, 6MWD, Accelerometry) • Potential surrogates : NT-pro-BNP; Not invasive hemodynamics

(risk); Imaging biomarkers

Conclusions

• Approval and development of PAH treatment in children : drugs, strategies

• Identification of a genetic profile slightly different from that of adults

• Registry data have grown substantially and inform for future trial design

• Pediatric specific trials are ongoing but new concepts should be developed to succeed

• A growing number of children transition to adult centers and this should be anticipated